A broad spectrum of respiratory diseases and disorders has been recognized and many of which have overlapping and interacting etiologies. Two of the most widespread and prevalent of these diseases are chronic obstructive pulmonary disorder (COPD) and asthma. Respiratory diseases have a significant inflammatory component. For example, current therapy for COPD and asthma focuses mainly on the reduction of symptoms using short and long acting bronchodilators either as monotherapies or combinations of long acting β2 agonist bronchodilators with inhaled corticosteroids (ICS).
COPD is a leading cause of morbidity and mortality worldwide with an overall prevalence in adults over 40 years currently estimated at between 9 and 10% (Halbert et al, Eur. Respir. J, 2006, 28(3):523-32). According to the World Health Organization (WHO), about 600 million people suffer from COPD, with some three million dying from the disease each year making it the third leading cause of mortality and fifth leading cause of morbidity in the world by 2020.
Clinical features of COPD include breathlessness, cough and sputum, with chronic airway obstruction and lung hyperinflation as a result of chronic bronchitis and emphysema (dilation of the distal lung airspaces). Chronic bronchial hyperactivity which is prominent in bronchial asthma is also found in COPD. Airway remodeling in COPD leads to persistent and irreversible airway narrowing and mucus hyper secretion. The direct cause of airway narrowing and hyper responsiveness is unknown although it is generally proposed that abnormalities in the airway smooth muscle function results in decreased or impaired relaxation or increased contractility.
COPD is a significant cause of death and disability. Treatment guidelines advocate early detection and implementation of smoking cessation programs to help reduce morbidity and mortality due to the disease. However, early detection and diagnosis has been difficult for a number of reasons.
COPD takes years to develop and smokers often deny any ill effects from smoking, attributing the early warning signs of increased breathlessness as a sign of age. Similarly, acute episodes of bronchitis often are not recognized by the general practitioner as early signs of COPD. Many patients exhibit features of more than one disease (e.g. chronic bronchitis or asthmatic bronchitis) making precise diagnosis a challenge, particularly in early disease. Also, many patients do not seek medical help until they are experiencing more severe symptoms associated with reduced lung function, such as dyspnea, persistent cough, and sputum production. As a consequence, the vast majority of patients are not diagnosed or treated until they are in a more advanced stage of disease.
Despite the recent advances that have been made in understanding the causes of respiratory disorders, they remain notoriously difficult to treat. From the foregoing, it can be seen that a need exists for identifying novel compounds for the prevention and treatment of respiratory disorders such as COPD and asthma.
Currently, COPD treatment focuses mainly on the reduction of symptoms using short and long acting bronchodilators either as monotherapies or combinations of long acting β2 agonist bronchodilators with inhaled corticosteroids (ICS). The disappointing anti-inflammatory data for ICS either alone or in combination with β2 agonists has intensified the search for an effective anti-inflammatory drug for COPD. One hypothesis under investigation is whether novel, demonstrably anti-inflammatory agents can halt or slow function decline characteristic of COPD. Reducing the frequency and severity of exacerbations has become an increasingly important target for COPD therapy as the prognosis for patients following exacerbations is poor. Anti-inflammatory therapy in COPD, and in asthma, is expected to reduce the frequency and severity of exacerbations, improve quality of life and perhaps reduce decline in lung function. Effective anti-inflammatory therapy in COPD may also produce an improvement in lung function.
Peroxisome Proliferation Receptor gamma receptor (PPARγ) agonists are a class of drug which increase sensitivity to glucose in diabetic patients and currently two PPARγ agonists are approved for clinical use in diabetes; Rosiglitazone and Pioglitazone. See Campbell I W, Curr Mol Med. 2005 May; 5(3):349-63. Both of these compounds are thiazolidinediones (TZDs), and are, in practice, administered by the oral route for systemic delivery. Physiological activation of PPARγ is believed to increase the sensitivity of peripheral tissues to insulin, thus facilitating the clearance of glucose from the blood and producing the desired anti-diabetic effect.
Unfortunately, PPARγ agonists also have unwanted cardiovascular effects, including haemodilution, peripheral and pulmonary oedema, and congestive heart failure (CHF). CHF is a complex clinical syndrome characterized by exertional dyspnea, fatigue and, often, peripheral edema resulting from left ventricular dysfunction (LVR). These unwanted effects are also believed to result from activation of PPARγ. In particular, a significant effort has been devoted to investigating the hypothesis that PPARγ agonists disturb the normal maintenance of fluid balance via binding to the PPARγ receptor in the kidney. See Guan et al, Nat Med. 2005; 11(8):861-6 and Zhang et al, Proc Natl Acad Sci USA. 2005 28; 102(26):9406-11. Treatment with PPARγ agonists by the oral route for systemic delivery is also associated with an unwanted increase in body weight.
In addition to their effects on glucose metabolism, a variety of reports have been published which demonstrate the potential of specific PPARγ agonists, such as Rosiglitazone, to exert anti-inflammatory effects. For instance, (i) Rosiglitazone has been reported to exert effects in diabetic patients consistent with an anti-inflammatory effect (Haffner et al, Circulation. 2002 August 6; 106(6):679-84, Marx et al, Arterioscler Thromb Vasc Biol. 2003 February 1; 23(2):283-8); (ii) Rosiglitazone has been reported to exert anti-inflammatory effects in a range of animal models of inflammation, including: carageenan-induced paw oedema (Cuzzocrea et al, Eur J Pharmacol. 2004 January 1; 483(1):79-93), TNBS-induced colitis (Desreumanux et al, J Exp Med. 2001 April 2; 193(7):827-38, Sanchez-Hidalgo et al, Biochem Pharmacol. 2005 June 15; 69(12):1733-44), experimental encephalomyelitis (Feinstein et al, Ann Neurol. 2002 June; 51(6):694-702) collagen-induced (Cuzzocrea et al, Arthritis Rheum. 2003 December; 48(12):3544-56) and adjuvant-induced arthritis (Shiojiri et al, Eur J Pharmacol. 2002 July 19; 448(2-3):231-8), carageenan-induced pleurisy (Cuzzocrea et al, Eur J Pharmacol. 2004 January 1; 483(1):79-93), ovalbumin-induced lung inflammation (Lee et al, FASEB J. 2005 June; 19(8):1033-5) and LPS-induced lung tissue neutrophilia (Birrell et al, Eur Respir J. 2004 July; 24(1):18-23) and (iii) Rosiglitazone has been reported to exert anti-inflammatory effects in isolated cells, including iNOS expression in murine macrophages (Reddy et al, Am J Physiol Lung Cell Mol Physiol. 2004 March; 286(3):L613-9), TNF□-induced MMP-9 activity in human bronchial epithelial cells (Hetzel et al, Thorax. 2003 September; 58(9):778-83), human airway smooth muscle cell proliferation (Ward et al, Br J Pharmacol. 2004 February; 141(3):517-25) and MMP-9 release by neutrophils (WO 0062766).
Based on observations of anti-inflammatory activity in cells relevant to the lung, the utility of PPARγ agonists in general has been disclosed for the treatment of inflammatory respiratory disorders including asthma, COPD, cystic fibrosis, pulmonary fibrosis (Refer patent applications WO00/53601, WO02/13812 and WO00/62766). These disclosures include administration by both the oral and inhaled routes.
COPD patients are known to be at a higher risk than other clinical populations from congestive heart failure (CHF) (Curkendall et al, Ann Epidemiol, 2006; 16: 63-70, Padeletti et al, Int J Cardiol. 2008; 125(2):209-15) and so it is important that systemic activation of the PPARγ receptors is kept to a minimum in these patients to avoid increasing the likelihood of CHF. Administering respiratory drugs by the inhaled route is one approach to target the lung with an anti-inflammatory agent whilst keeping systemic exposure of the drug low, reducing the likelihood of systemic activity and observation of side effects.
Therefore, taking into account the potential anti-inflammatory utility of PPARγ receptor agonists in the treatment of respiratory disease, and weighing that potential utility against the undesirable side effects of high systemic exposure to this drug class, there is a need for PPARγ receptor agonists that are effective in treating such diseases, have physico-chemical properties rendering them suitable for pulmonary delivery by inhalation, and have low systemic exposure following inhalation.
Systemic exposure of an inhaled drug is generally achieved by two methods. Following oral inhalation of a respiratory drug 10-50% of the dosage delivered by the device (e.g. inhaler or nebuliser) is delivered to the respiratory tract where it can achieve its desired pharmacological action in the lungs. Ultimately, any drug that has not been metabolized by the lungs, is delivered by the lungs to the systemic circulation. Once the active drug is present in the circulation, the clearance rate of the drug from the plasma is critical to its systemic activity. Therefore, a desired property of an inhaled drug for the treatment of lung disease is to have low plasma area under the curve (AUC) relative to the dose administered as this will limit systemic pharmacological activity and thus reduce likelihood of side effects. The suitability of different compounds in this regard can be assessed by determining the plasma AUC following .i.v. dosing at equivalent dosages. Compounds suitable for inhalation for the treatment of lung disease will have a low plasma AUC and compounds likely to have a propensity for systemic side effects will have a higher plasma AUC.
Following oral inhalation of a respiratory drug, the other 50-90% of the inhaled dose is swallowed. Therefore, another method of reducing systemic exposure by an inhaled drug is for the drug to have reduced oral bioavailability (ability of the GI tract to absorb intact drug and deliver it to the circulation). A compound having low oral bioavailability will have significantly lower plasma exposure as measured by plasma AUC following oral dosing than when an equivalent dosage of the same compound is administered by the intravenous (i.v.) route.